Method for treating mucositis by sublingual administration of DNA

ABSTRACT

Methods for treating mucositis are presented. An effective amount of DNA is administered to a patient with mucositis sublingually in a manner that does not cause gene transfer but does cause a reduction in viscosity of mucous or sputum.

This application is a continuation-in-part of U.S. patent applicationSer. No. 08/755,092 filed Nov. 22, 1996, issued Mar. 10, 1998 as U.S.Pat. No. 5,726,160 which is a continuation of U.S. patent applicationSer. No. 08/421,232 filed Apr. 13, 1995, now abandoned.

FIELD OF THE INVENTION

The present invention relates to methods for treatment of pulmonarydisorders.

BACKGROUND OF THE INVENTION

The present invention provides methods for treatment of pulmonarydiseases. Such diseases, including cystic fibrosis, emphysema, chronicbronchitis, sinusitis, and the common cold, have in common bronchial orsinus congestion, production of large amounts of sputum, and thepossibility of secondary bacterial infection requiring antibiotictherapy. The most serious of those diseases is cystic fibrosis, agenetic disorder of exocrine function characterized by abnormallyviscous mucus secretions leading to chronic pulmonary obstruction,pancreatic insufficiency and elevated sweat sodium and chloride levels.Cystic fibrosis is often fatal. The viscosity of sputum produced bycystic fibrosis patients is thought to be due to its high content ofDNA. Diseases such as bronchitis, emphysema, sinusitis, and the commoncold are generally less severe than cystic fibrosis, but those diseasesalso may result in production of large amounts of sputum. Still otherpulmonary diseases include mucositis (inflammation of the mucosalmembranes) which is frequently associated with radiation therapy andwhich is characterized by production of a thick water deficient mucouswhich is difficult for the subject to eliminate.

Other pulmonary diseases include chronic obstructive pulmonary diseases(COPDs) which share the common feature of chronic expiratory airflowlimitation i.e., persistent slowing of the rate at which exhalation canbe achieved. Common COPDs include chronic bronchitis, emphysema andasbestosis and are characterized by respiratory distress but notassociated with aberrant mucous accumulation. Cigarette smoke is themost common cause of COPDs which are also associated with exposure torespirable dusts particularly in workplace environments of those engagedin occupations such as gold and coal mining, textile manufacturing andcement and steel making.

As with cystic fibrosis, other pulmonary diseases frequently lead tosecondary bacterial infections. Treatment of pulmonary diseasesgenerally requires antibiotic therapy which is frequently ineffective.Recently, however, cystic fibrosis has been treated using DNase. Therationale for such therapy is that degrading DNA in sputum reduces theviscosity of the sputum and results in an increased ability of thepatient to evacuate sputum from the lungs and nasal passages. However,no known report advocates using DNA itself as a treatment for anypulmonary infection or condition.

SUMMARY OF THE INVENTION

The present invention provides methods for treating respiratory illness.Specifically, the invention provides methods for treating symptoms ofrespiratory distress not associated with aberrant mucous accumulation ina patient, comprising the step of administering in a manner so as not toeffect gene transfer an effective amount of DNA in apharmaceutically-acceptable vehicle to a patient having a diseasecharacterized by respiratory distress not associated with aberrantmucous accumulation including but not limited to diseases such aschronic obstructive pulmonary disease including bronchitis, emphysemaand asbestosis as well as asthma.

The invention further provides methods for relieving respiratorycongestion in a patient as a result of overproduction of viscous mucusor sputum lodged in the patients's respiratory tract due to conditionsincluding mucositis such as caused by radiation comprising the steps ofadministering in a manner so as not to effect gene transfer atherapeutically effective amount of DNA in a pharmaceutically-acceptablevehicle to a patient having a disease characterized by respiratorycongestion, wherein said respiratory congestion is a result of anoverproduction of viscous mucus or sputum lodged in said patients'srespiratory tract, and wherein said method results in the reducedviscosity of said mucus or said sputum such that there is an increase ofproduction and a reduced accumulation of mucus in said patient'srespiratory tract.

Methods of the invention comprise administration to a patient sufferingfrom respiratory distress an effective amount of DNA. The DNA ispreferably provided in an amount ranging from about 0.00012 mg to about0.003 mg and is preferably formulated in a liquid vehicle and providedat a concentration of approximately 0.0006 mg as single drops. Apreferred route of administration is sublingual, but other routes, suchas subcutaneous, intravenous, intramuscular, and intrathecal areexpected to work. DNA for use in the present invention may beprokaryotic DNA or eukaryotic DNA and may be formulated in a number ofpharmaceutically-acceptable vehicles, including water, saline, albumin,and dextrose.

Additional aspects and advantages of the invention will become apparentupon consideration of the following detailed description thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods for treating patients withsymptoms of respiratory distress not associated with aberrant mucousaccumulation in a patient including symptoms resulting from chronicobstructive pulmonary diseases such as chronic bronchitis, emphysema, byadministering to such patients a small amount of DNA in a manner so asnot to effect gene transfer. Methods of the invention are also usefulfor treating pulmonary congestion in patients having any disease inwhich mucus production is a symptom and are especially effective intreating diseases wherein viscous mucus or sputum is produced andbecomes lodged in a patient's respiratory tract. In those cases, methodsof the invention reduce production of DNA in a patient's mucussecretions and thereby render mucus less viscous, allowing for increasedproduction away from the respiratory tract.

Methods according to the invention for treating pulmonary congestionhave been tested in clinical trials with human patients having variousrespiratory disorders, including cystic fibrosis, bronchitis, andemphysema using calf thymus DNA (Sigma, St. Louis). In each case,patients are administered sublingual drops of DNA at a concentration ofabout 0.0006 mg DNA per drop. No other therapy was conducted in anypatient during the course of DNA therapy. As noted below, all patientstested showed improvement in mucus production (i.e. sputum was easier todislodge) from the respiratory tract. In addition, sputum was lessviscous as compared to pretreatment levels. Reduced sputum viscosityleads to increased patient comfort, increased ability of the patient tobreathe, and reduced risk of secondary bacterial infection. No adverseside effects were observed in any patients. Drops of DNA may beadministered at the appropriate concentration in doses of 1 to 10 dropsper day as required by the patient. For each Example below, calf thymusDNA (Sigma) was used.

The following Examples illustrate the preferred embodiments of theinvention and provide evidence of the effectiveness of claimed treatmentmethods. Numerous improvements and further aspects of the invention areapparent to the skilled artisan upon consideration of the Examples whichfollow.

EXAMPLE I

Twenty-three year-old twin brothers presented with cystic fibrosis. Eachhad a history of hospitalizations for lung clearance and secondaryinfections diagnosed as being associated with their cystic fibrosis.Each patient began therapy with 1-2 drops (0.0006 mg/drop) of DNAsublingually per day. For almost two years since beginning DNA therapy,neither patient has been hospitalized. In addition, follow-upevaluations by physicians revealed a 30-45% increase in airflow in eachpatient. Moreover, forced vital capacity, a common measure of lungcapacity and the extent of mucus clearance in the lungs, increased from60-90%. Finally, each of the brothers has gained weight and has shownincreased expectoration.

After approximately one year of therapy, one of the brothers stoppedtaking the DNA drops. His condition steadily worsened as a result, withincreased mucus viscosity, decreased forced vital capacity and reducedexpectoration. That patient then began taking drops of DNA at theprescribed dose and immediately improved to the condition he was inprior to the time at which he stopped taking the drops.

EXAMPLE II

A 64-year-old female patient who suffered from emphysema and bronchitis,as diagnosed by her physician, was placed on a dose of 1 drop per day(0.0006 mg/drop) of DNA sublingually. Within one week, a follow-upevaluation revealed that her mucus production was less viscous andexpectoration was increased.

EXAMPLE III

A 25-year-old female diagnosed with chronic upper respiratory illnesswas treated with methods according to the invention. Previous antibiotictherapy was unsuccessful in treating her condition. She began with 1drop of DNA (0.0006 mg/drop) sublingually four times per day. Within oneday, she experienced an increase in expectoration and, after three daysshe was able to discontinue treatment, having been completely relievedof congestion. She has remained symptom free.

EXAMPLE IV

A 32-year-old female nurse presented with a severe upper respiratoryinfection and unproductive respiratory congestion. She was placed on 1drop of DNA (0.0006 mg/drop) four times per day. Her congestion began tobreak up almost immediately. Expectoration was improved and thepatient's illness resolved after 4.5 days and no congestion recurred.

EXAMPLE V

A 63-year-old woman presented with chronic sinusitis. Four drops of DNAper day were administered. After 3 months, the patient's mucus hadthinned and her cough was more productive.

EXAMPLE VI

A 37-year-old female presented with unresolved respiratory congestion.Traditional therapy, including expectorants, failed to improve hercondition. The patient was then prescribed four drops of DNA (0.0006mg/drop) per day. After one day of treatment, her congestion was moreproductive and sinus drainage had begun where none was present prior totreatment according to the invention.

EXAMPLE VII

A 40-year-old woman with unproductive upper respiratory congestion wasplaced on 4 drops of DNA (0.0006 mg/drop) per day. Her congestion wasmore productive after one day and she continued to expectorate freely.In this case, therapy was supplemented with an over-the-counterexpectorant.

EXAMPLE VIII

A 38-year-old woman with acute and chronic respiratory disease due toexposure to toxic corrosive materials was treated with methods accordingto the invention. Prior to such treatment, symptoms, including chronicrhinorrhea, chest congestion and chronic respiratory infections weretreated with numerous courses of antibiotics without success. Thepatient began treatment with 0.5 cc Q.I.D. daily and was instructed toadminister treatment up to 5-6 times daily if necessary.

Upon commencing treatment according to the invention, the patient wasable to produce sputum almost immediately. Continued treatment hasalleviated symptoms of chronic respiratory illness.

EXAMPLE IX

A 58-year-old woman diagnosed with a childhood history of asthma andpersistent adult rhinitis and sinusitis presented for treatment.Physical examination indicated clear rhinorrhea, and 3+ red throat.Nasal spray and prednisone were prescribed for 7 days. That course oftreatment resulted in mild improvement. However, the patient's cough wasstill unproductive. Therapy according to the invention was begun at 0.5cc Q.I.D. Within 48 hours, the patient showed improvement in the form ofa productive cough and sinus drainage.

EXAMPLE X

A 48-year-old woman with chronic sinusitis and bronchitis characterizedby chronic head congestion, nasal obstruction, and coughing presentedfor treatment according to the invention. The patient was treatedaccording to the invention with one drop per day of DNA (0.0006mg/drop). Treatment resulted in an overt increase in sinus and chestdrainage. Upon cessation of treatment according to the invention, thepatient's condition regressed. Beginning therapy again caused a similarincrease in drainage and relief of congestion as seen previously withtreatment according to the invention.

The following examples report the results of treatment of subjectssuffering from radiation induced mucositis with the DNA containingcompositions of the invention.

EXAMPLE XI

According to this example, a subject suffering from radiation inducedmucositis was treated with one drop of DNA (0.0006 mg/drop) sublinguallyfour times per day. The subject experienced a 50% improvement withphlegm thickness and had less cough. Experimentation by the subject withdosage frequency revealed that administration of one drop alone wasinsufficient but that administration of three to four drops per dayappeared to be optimal.

EXAMPLE XII

According to this example, a subject suffering from radiation inducedmucositis was treated with one drop of DNA (0.0006 mg/drop) sublinguallyfour times per day. While treatment with four drops per day did notprovide subjective improvement an increase in dosage to ten drops perday may have resulted in less phlegm. The subject discontinuedadministration of DNA but restarted use later and reported thinning ofphlegm. The formulation was later modified to include 2 units ofstreptolysin O per drop although it could not be determined ifincorporation of streptolysin 0 improved the therapeutic results.

EXAMPLE XIII

According to this example, a subject suffering from radiation inducedmucositis was treated with one drop of DNA (0.0006 mg/drop) sublinguallyfour times per day with the result of a 50% improvement in phlegmthickness. In addition the subject noted that her sense of tasteimproved from nonexistent to normal.

The following examples report the results of treatment of three patientssuffering with mild to moderate chronic obstructive pulmonary diseasenot characterized by aberrant mucous accumulation who were successfullytreated with DNA containing compositions according to the methods of theinvention.

EXAMPLE XIV

A 67 year-old male former smoker with a medical history of gout,hypertension, peptic ulcer and chronic obstructive pulmonary diseasepresented with shortness of breath during high humidity, walking up ahalf flight of stairs, walking in the yard and at night laying flat inbed. The subject suffered from minimal phlegm production which was whitein color. The subject was being treated with allopurinol, Pepcid(famotidine), Slobid (theophylline), Calan (verapamil HCI), Accupril(quanapril HCI) and Albuterol Inhaler. A pre-study office spirometryshowed moderate COPD with an Fev1 % of 51.

The subject was treated with 1 drop of DNA (0.0006 mg/drop) sublinguallyfour times per day. After fourteen days of treatment the subjectreported that his overall dyspnea had improved from a subjective ratingof a 10 to a 4. He was able to walk at the mall without shortness ofbreath where previously, he had to stop. A spirometry on day 16 showedno change but three months later with continued treatment according tothe invention could ascend 13 steps where prior to treatment he had beenunable to ascend only half as many steps without dyspnea. The subjectwas also able to decrease Albuterol administration from daily to 2-3times weekly and eventually to once in four weeks and discontinue use ofSlobid. The subjects wife reported that the subject's sleep is morerestful and that she no longer hears wheezing at night.

EXAMPLE XV

A 71 year-old female with a medical history of hypertension, myocardialinfarction, renal insufficiency, hiatal hernia, spinal stenosis,hyperlipidemia and chronic obstructive pulmonary disease presented withshortness of breath while cooking meals, walking 17 steps, carryinglaundry, vacuuming, making her bed, walking to the car, and in the mall.She also complained of minimal phlegm. She was undergoing treatment withmedications including Cardizem CD (ditiazem HC1), Vasotec (enalaprilat),Zocor (simvastatin), Ogen (estropripate), Zantac (ranitidine HC1),Toprol (metoprolol succinate), Nitroglycerine patch, LorTab (hydrocodonebitartrate and aspirin), and a sleep agent as required. Uponexamination, she had mild anterior wheezing and a pre-study officespirometry showed an Fev1 of 70.

The subject was treated with 1 drop of DNA (0.0006 mg/drop) sublinguallyfour times per day. After seven days of treatment the subject reportedno improvement but fourteen days of treatment reported that she couldwalk in the mall without shortness of breath and was vacuuming andmaking her bed without needing to stop and rest. A repeat spirometryafter fourteen days showed an Fev1 % of 78, an 11% improvement from thepre-study result. The subject's condition continued to improve exceptwhen she decreased the treatment schedule to once per day and hershortness of breath returned. After increasing back to treatment fourtimes daily her dyspnea resolved to the extent that she was able todiscontinue her use of a Serevent (Glaxo) aerosol inhaler after fourmonths.

EXAMPLE XVI

A 76 year-old female with a medical history of hypertension, arrhythmia,hypercholesterolemia, chronic obstructive pulmonary disease (for atleast ten years) and anxiety presented with dyspnea after climbing oneflight of stairs, exertional dyspnea and cough and with minimal phlegm.The subject was being treated with Normodyne (labetalol HCI), Procardia(nifedipine), Persantine (dipyridamole), Zocor (simvastatin), AtroventInhaler (ipratropium bromide) and Xanax (aprazolam). Upon examination,she had moderately decreased lung sounds with normal blood pressure. Aspirometry conducted ten years previously showed an Fev1 % of 73(normal) with diminished mid flow rates suggesting early COPD.

The subject was treated with 1 drop of DNA (0.0006 mg/drop) sublinguallytwice daily and after one month of treatment had less coughing anddiminished wheezing at home when in bed. A spirometry after almost twomonths of treatment showed an Fev1 % of 65. The subject continued toreport subjective improvement and stopped administration of Atrovent.After four months wheezing was nearly gone and her cough was less thanprior to treatment according to the invention.

EXAMPLE XVII

According to this example, several asthma patients were treated by dailyadministration of at least one drop of DNA (0.0006 mg/drop) derived fromeither salmon sperm or bovine sources. Follow-up evaluation of thosesubjects showed decreased viscosity and volume of sputum. In addition,the salmon sperm DNA was found to have therapeutic activity equivalentto that of the bovine derived DNA.

EXAMPLE XVIII

According to this example, a 56 year old non-smoker with chronicobstructive pulmonary disease/emphysema secondary to asbestosis andtotal disability due to pulmonary insufficiency was treated bysublingual administration of at least one drop of DNA (0.0006 mg/drop)four times daily. After a few weeks of treatment the subject reportedfeeling "dramatically better" and "not out of breath." The subject hassince reduced the frequency of treatment to one drop daily.

The invention has been described in terms of its preferred embodimentsand is only intended to be limited by the scope of the following claims.

What is claimed is:
 1. A method for treating mucositis of therespiratory tract in a patient comprising the step of administeringsublingually and in a manner so as not to effect gene transfer andexpression, a therapeutically effective amount of DNA in apharmaceutically acceptable vehicle to a patient having mucositis of therespiratory tract characterized by overproduction of viscous mucous orsputum lodged in said patient's respiratory tract, and wherein saidmethod results in the reduced viscosity, increased elimination and/ordecreased accumulation of said mucus or said sputum.
 2. The methodaccording to claim 1, wherein said vehicle is selected from the groupconsisting of water, saline, albumin, or dextrose.
 3. The methodaccording to claim 1, wherein said effective amount of DNA is from0.00012 mg to about 0.003 mg DNA.
 4. The method according to claim 1,wherein said effective amount of DNA is 0.0006 mg of DNA.
 5. The methodaccording to claim 1, wherein said patient is a human.